1. Field of the Invention
This invention relates to a method of treating atrial arrhythmias that minimizes undesirable side effects, comprising administration of an adenosine A1 receptor agonist in low doses.
2. Background Information
Atrial arrhythmias, such as primary atrial fibrillation, atrial flutter, and paroxysmal atrial tachycardia (PSVT), are abnormal heart rhythms that are due to a variety of factors. Arrhythmias can range from incidental, asymptomatic clinical findings to life-threatening abnormalities. Arrhythmias account for a significant percentage of the causes of death in human. Thus, it is desirable to develop methods of mitigating the effects of arrhythmia.
A variety of anti-arrhythmic drug therapies are presently available. These compounds, however, have significant limitations. Digoxin, for example, has a delayed onset of action (about 30 min) and its peak effects are not observed for 3 to 4 hours after administration. Other examples are xcex2-blockers and calcium-channel blockers, which widely used to treat arrhythmias, can cause hypotension and have negative inotropic effects.
Adenosine is a naturally occurring compound that is highly effective in ameliorating arrhythmia. However, adenosine has a wide variety of physiological effects. The multiple activities of adenosine are mediated by its interactions with a family of adenosine receptors, known as the adenosine A1, A2A, A2B, and A3 receptors, each of which regulates distinct biological activites. For example, adenosine binds to adenosine A1 receptors in heart resulting in a dromotrophic effect while the binding of adenosine to A2A results in coronary vasodilation. Likewise adenosine binds to adenosine A2B receptors thus affecting a wide array of activities including angiogenesis, cellular proliferation, and apopotosis, to name a few. On the other hand, adenosine binds toA3 receptors on mast cells thereby stimulating degranulation and the release of histamine.
The anti-arrhythmic effects of adenosine are due exclusively to its interaction with the adenosine A1 receptor subtype. However, contemporaneous binding of adenosine to the subtypes, A2A, A2B, and A3 results in undesirable side effects, such as vasodilation, changes in the heart rate and mast cell degradation. Thus, the lack of selectivity of adenosine for the A1 receptor subtype makes adenosine unsuitable for the treatment of arrhythmias. Additionally, adenosine has a short half-life (xcx9c10 sec) making it ineffective in any condition that requires prolonged drug action.
Thus, there is a need for a method of treating arrhythmias with therapeutic agents that are selective for the adenosine A1 receptor, have sufficiently long half-lives, and have few side effects. Preferred compounds would be active at very low doses, since lower doses provide less opportunity for side effects.
New classes of agonists that bind to adenosine A1 receptors and that are useful in treating arrhythmias are disclosed in U.S. Pat. No. 5,789,416, the entire disclosure of which is hereby incorporated by reference. These compounds have a high specificity for the adenosine A1 receptor subtypes, but like all therapeutic compounds, can potentially cause side effects.
The effective dose of the compounds of ""416 is disclosed to be in the range of 0.01-100 mg/kg. Surprisingly, we have discovered that the compounds are active at much lower doses (0.0003-0.009 mg/kg) than those disclosed as effective in ""416. Accordingly, a novel and effective method of treating arrhythmias is provided that restores sinus rhythm without slowing the sinus rate and is virtually free of undesirable side effects, such as changes in mean arterial pressure, blood pressure, heart rate, or other adverse effects.
It is an object of this invention to provide an effective method of treating atrial arrhythmias in a mammal while minimizing undesirable side effects. Accordingly, in a first aspect, the invention relates to a method of treating atrial arrhythmias in a mammal comprising administration of a therapeutically minimal dose of an adenosine A1 receptor agonist of Formula I to a mammal in need thereof: 
Wherein:
R1 is an optionally substituted heterocyclic group, preferably monocyclic; and said minimal dose is in the range of 0.0003-0.009 mg/kg.
In a more preferred embodiment, R1 is 3-tetrahydrofuranyl, 3-tetrahydrothiofuranyl, 4-pyranyl and 4-thiopyranyl.
The compounds of Formula I exist as a racemic mixture, or as individual isomers. Most preferred is 6-(3-(R)-aminotetrahydrofuranyl) purine riboside.
The most preferred embodiment of the invention is a method of treating atrial arrhythmias in a mammal comprising administering a therapeutically minimal dose of 0.0003-0.009 mg/kg of 6-(3-(R)-N-aminotetrahydrofuranyl) purine riboside, hereafter referred to as CVT-510.